Genetic Variant SEMA6A:p.Gln970Pro (chr5-116446797-T-G) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_020796.5(SEMA6A):c.2909A>C(p.Gln970Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00573 in 1,613,124 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0042 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0059 ( 31 hom. )

Consequence

SEMA6A
NM_020796.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.73

Variant links:

Genes affected

SEMA6A (HGNC:10738): (semaphorin 6A) Predicted to enable identical protein binding activity; signaling receptor binding activity; and transmembrane signaling receptor activity. Involved in cellular response to vascular endothelial growth factor stimulus; negative regulation of cell adhesion involved in sprouting angiogenesis; and negative regulation of signal transduction. Predicted to be integral component of membrane. Predicted to be active in extracellular space. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SEMA6A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007560551).

BP6

Variant 5-116446797-T-G is Benign according to our data. Variant chr5-116446797-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 718147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 31 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA6A	NM_020796.5 link	c.2909A>C	p.Gln970Pro	missense_variant	Exon 19 of 19	ENST00000343348.11	NP_065847.1	Q9H2E6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA6A	ENST00000343348.11 link	c.2909A>C	p.Gln970Pro	missense_variant	Exon 19 of 19	1	NM_020796.5	ENSP00000345512.6		Q9H2E6-1

Frequencies

GnomAD3 genomes

AF:

0.00421

AC:

640

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00584

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00691

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00470

AC:

1159

AN:

246662

AF XY:

0.00464

show subpopulations

Gnomad AFR exome

AF:

0.00119

Gnomad AMR exome

AF:

0.00146

Gnomad ASJ exome

AF:

0.00722

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00771

Gnomad NFE exome

AF:

0.00720

Gnomad OTH exome

AF:

0.00334

GnomAD4 exome

AF:

0.00589

AC:

8600

AN:

1460838

Hom.:

Cov.:

AF XY:

0.00582

AC XY:

4231

AN XY:

726622

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

AC:

AN:

33464

Gnomad4 AMR exome

AF:

0.00159

AC:

AN:

44570

Gnomad4 ASJ exome

AF:

0.00801

AC:

209

AN:

26104

Gnomad4 EAS exome

AF:

0.0000252

AC:

AN:

39686

Gnomad4 SAS exome

AF:

0.000975

AC:

AN:

86144

Gnomad4 FIN exome

AF:

0.00786

AC:

419

AN:

53330

Gnomad4 NFE exome

AF:

0.00671

AC:

7458

AN:

1111452

Gnomad4 Remaining exome

AF:

0.00545

AC:

329

AN:

60324

Heterozygous variant carriers

588

1175

1763

2350

2938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

270

540

810

1080

1350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00420

AC:

640

AN:

152286

Hom.:

Cov.:

AF XY:

0.00396

AC XY:

295

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00125

AC:

0.00125096

AN:

0.00125096

Gnomad4 AMR

AF:

0.00124

AC:

0.00124199

AN:

0.00124199

Gnomad4 ASJ

AF:

0.00720

AC:

0.00720461

AN:

0.00720461

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00104

AC:

0.00103691

AN:

0.00103691

Gnomad4 FIN

AF:

0.00584

AC:

0.00583584

AN:

0.00583584

Gnomad4 NFE

AF:

0.00691

AC:

0.00690973

AN:

0.00690973

Gnomad4 OTH

AF:

0.00284

AC:

0.00283822

AN:

0.00283822

Heterozygous variant carriers

108

144

180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00612

Hom.:

Bravo

AF:

0.00379

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.00120

AC:

ESP6500EA

AF:

0.00733

AC:

ExAC

AF:

0.00445

AC:

539

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SEMA6A: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.032

.;T;T;.;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

.;D;D;D;.

M_CAP

Benign

0.013

MetaRNN

Benign

0.0076

T;T;T;T;T

MetaSVM

Benign

-0.95

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.2

N;N;N;N;N

REVEL

Benign

0.23

Sift

Uncertain

0.012

D;D;D;D;D

Sift4G

Benign

0.15

T;T;D;D;T

Polyphen

0.96, 0.94

.;.;D;P;.

Vest4

0.59

MVP

0.41

MPC

0.71

ClinPred

0.026

GERP RS

4.3

gMVP

0.51

Mutation Taster

=92/8

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over